Glucosamine-6-phosphate synthase (GlmS)

Glucosamine-6-phosphate synthase is a pivotal enzyme that catalyzes the first and rate-limiting step of the hexosamine biosynthetic pathway (HBP), converting fructose-6-phosphate and glutamine into glucosamine-6-phosphate (Milewski, 2002). In prokaryotes and fungi, where it is commonly known as GlmS, the enzyme is essential for producing UDP-N-acetylglucosamine, a vital precursor for the synthesis of peptidoglycan and chitin in cell walls (Teplyakov et al., 1999). Because of its essentiality in microbes and its distinct structural features compared to human counterparts, GlmS is a major target for the development of antibacterial and antifungal agents (Wojciechowski et al., 2005). In humans, the enzyme is referred to as glutamine-fructose-6-phosphate aminotransferase (GFAT) and serves as a key nutrient sensor that regulates glucose homeostasis and protein O-GlcNAcylation (Chiaradonna et al., 2018). Dysregulation of GFAT is closely associated with the development of insulin resistance, type 2 diabetes, and the metabolic reprogramming observed in various cancers (Marshall et al., 1991). Pharmacological targeting of this enzyme typically involves glutamine analogues or transition-state mimetics that inhibit the glutamine-binding site or the isomerase domain (Milewski, 2002). However, the high degree of conservation in the active site across species poses a significant challenge for achieving the selectivity required to minimize host toxicity in antimicrobial applications (Bearne & Blouin, 2000).

Other names

Glutamine--fructose-6-phosphate aminotransferase [isomerizing]GFATGFPT1GFPT2Hexosephosphate aminotransferaseL-glutamine:D-fructose-6-phosphate aminotransferase

Competitive or irreversible inhibition of the glutamine-binding site or the isomerase domain, preventing the conversion of fructose-6-phosphate and glutamine into glucosamine-6-phosphate.